Background: Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but\r\nthe biochemical details and underlying mechanisms of these disorders have not been defined.\r\nMethods: Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4\r\ncounts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas\r\nchromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered\r\nlipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined.\r\nUnsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis\r\n(PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using\r\ndChip, Metaboanalyst, and MSEA software.\r\nResults: A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV\r\npatients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery\r\nrate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and\r\neicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of\r\naltered lipids correlated with markers of inflammation (interferon-a and interleukin-6), microbial translocation\r\n(lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations\r\nshowed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids\r\nwere associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with\r\nacylcarnitines, a marker of mitochondrial dysfunction.\r\nConclusions: Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation,\r\nmicrobial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate\r\nimmune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders\r\nin HIV patients.
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